PROJECT SUMMARY/ABSTRACT Posttraumatic Stress Disorder (PTSD) is a debilitating disease affecting millions of American military veterans and civilians. Prolonged Exposure (PE) therapy is evidence-based and effective but limited by high dropout rates and incomplete resolution of symptoms in approximately one-third of patients. A crucial component of PE, as well as interventions for anxiety disorders, is ?In Vivo Exposure? (IVE) during which patients approach safe but avoided stimuli in the ?real world.? Typically, patients are given in vivo assignments to complete in-between therapy sessions, which leaves providers reliant upon patient self-report and may increase risk for patient disengagement and dropout. At present, there are no digital technology systems that target IVE. The proposed study directly addresses this critical gap by using intelligent biometrics (IB) to personalize and optimize IVE. The new system (IB-PE) includes a multidimensional data acquisition and storage system to capture real-time biomarkers of engagement (e.g., heart rate, skin conductance) and self-report (e.g., subjective units of distress or SUDS) during IVEs, enabling therapists to virtually accompany patients during IVEs (without leaving the office) and modify the exercises based on objective biometrics of activation to ensure maximal efficiency and therapeutic benefit, thereby eliminating traditional shortcomings of standard PE. Furthermore, the system will record IVEs for offline analysis. Key innovations are that?for the first time?clinicians will be able to participate in the IVE experience from the office, use real-time biometrics to optimize IVEs and minimize patient under- or over-engagement, and have the benefit of reviewing IVEs offline to guide treatment planning. This Phase 1 project will: (1) Integrate physiological biomarker sensors with SUDS and audio/visual streaming into a system for office-based therapists to use during IVE; (2) Determine feasibility and acceptability of the new system by measuring ease of use, comfort and utility in a real-world environment; and (3) Conduct a 12-session randomized clinical trial in 40 veterans with PTSD to evaluate preliminary efficacy of IB-PE in reducing PTSD severity from baseline to session 12. In addition, recorded IVE sessions will be analyzed to identify biological and behavioral indicators with high predictive value of treatment response. At the conclusion of this project, a comfortable and unobtrusive system will be ready for larger definitive trials of IB-PE. It is expected that the IB-PE system will, through technology-enabled human support and guidance, result in clinically significant reduction of PTSD symptoms achieved with fewer sessions, thereby lowering costs and improving access. This application is directly responsive to the FOA (PA-18-579) encouraging STTR grant applications to support research and development of priority research topics - complex technologies that require funding levels and durations beyond those reflected in the standard STTR guidelines. The findings from this study have the potential to innovate and transform clinical practice, and significantly improve exposure therapy for PTSD.